Pulmonary Zygomycosis in a Non-neutropenic Patient With Myelodysplastic Syndrome on Lenalidomide

Discussion

This is a case of pulmonary zygomycosis in a non-neutropenic patient with MDS. Pulmonary zygomycosis is an uncommon infection that occurs most often, but not exclusively, in immunocompromised patients. This patient did not have diabetes mellitus and was not neutropenic on presentation, with an absolute neutrophil count of 2,387 cells/μL. MDS has been associated with fungal infections, although most often in patients who have received induction chemotherapy or have prolonged or severe neutropenia.^4,5 He was started on lenalidomide 3 months prior to presentation, which is a tumor necrosis factor-alpha inhibitor 50,000 times more potent than thalidomide.⁶ This anti-tumor necrosis factor-alpha effect may increase the risk for fungal infections, even in non-neutropenic patients.⁷ This potential increased risk for fungal infections in non-neutropenic patients on lenalidomide is important for oncology and pulmonary physicians to consider when initiating therapy and managing subsequent fevers and infections.

This case also illustrates the difficulty in diagnosing pulmonary zygomycosis. This patient had a BAL with no evidence of fungal infection and negative assays for (1,3)-B-D-glucan and aspergillus galactomannan antigen. However, the role of BAL in the diagnosis of pulmonary zygomycosis remains incompletely studied. A case series by Glazer et al in 2000 examined 5 patients diagnosed with pulmonary mucormycosis and found microscopy of BAL was positive in 3 of 5 patients, and BAL fungal culture was positive in only 1 of 5 patients.⁸ (1,3)-B-D-glucan assay and aspergillus galactomannan antigen are negative in zygomycosis because of limited glucan and galactomannan in their cell wall.⁹ Often a tissue sample is required to make the diagnosis. Commonly employed techniques of obtaining tissue include transbronchial biopsy, imaging guided biopsy, or open surgical biopsy. Unfortunately, this patient was at high risk for complications and thus a biopsy was deferred. Given the limited sensitivity of BAL, lack of cell-wall markers, and the frequent need for a biopsy, the diagnosis of pulmonary zygomycosis is difficult and often delayed. This delay likely contributes to the 76% mortality rate of pulmonary zygomycosis,³ because zygomycosis is not susceptible to voriconazole and the echindocandins, which are often used for empiric antifungal coverage. In this patient the treatment of choice, liposomal amphotericin B (with posaconazole emerging as a new option), was empirically instituted too late to alter the disease course.¹⁰

Another important aspect in the treatment of pulmonary zygomycosis is surgical management. A combination of surgical resection and antifungal management is associated with a mortality benefit in the treatment of pulmonary zygomycosis over medical management alone.^11,12 In this patient, surgery was not pursued because the surgical risk was high and the diagnosis was not known until post-mortem.

Finally, to the best of our knowledge, this is the first time post-mortem transbronchial lung biopsy has been used without a concurrent autopsy. In this case the family declined full autopsy, which would have been helpful in determining the etiology of the consolidation as well as determining if dissemination had occurred. The family did agree to a less invasive transbronchial lung biopsy, which revealed zygomycetes. This is highly suggestive of pulmonary zygomycosis; however, we cannot entirely rule out colonization. The technique of post-mortem transbronchial biopsy may be a useful alternative in select patients when autopsy is declined.